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Molecular Characterization of the MLL-SEPT6 Fusion Gene in Acute Myeloid Leukemia

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Molecular Characterization of the MLL-SEPT6 Fusion Gene in Acute Myeloid Leukemia Brief Report Molecular characterization of the MLL-SEPT6 fusion gene in acute myeloid leukemia: identification of novel fusion transcripts and cloning of genomic breakpoint junctions Nuno Cerveira,1 Francesca Micci,2 Joana Santos,1 Manuela Pinheiro,1 Cecília Correia,1 Susana Lisboa,1 Susana Bizarro,1 Lucília Norton,3 Anders Glomstein,4 Ann E. Åsberg,5 Sverre Heim,2,6 and Manuel R. Teixeira1,7 1Department of Genetics, Portuguese Oncology Institute, Porto, Portugal; 2Section for Cancer Cytogenetics, Department of Medical Genetics, Radiumhospitalet-Rikshospitalet Medical Center, Oslo, Norway; 3Department of Pediatrics, Portuguese Oncology Institute, Porto, Portugal; 4Department of Pediatrics, Radiumhospitalet- Rikshospitalet Medical Center, Oslo, Norway; 5Department of Pediatrics, St Olav University Hospital, Trondheim, Norway; 6Faculty Division, The Norwegian Radium Hospital, Medical Faculty, University of Oslo, Norway and 7Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal Citation: Cerveira N, Micci F, Santos J, Pinheiro M, Correia C, Lisboa S, Bizarro S, Norton L, Glomstein A, Åsberg AE, Heim S, and Teixeira MR. Molecular characterization of the MLL-SEPT6 fusion gene in acute myeloid leukemia: identification of novel fusion transcripts and cloning of genomic breakpoint junctions. Haematologica 2008; doi: 10.3324/haematol.12594 positive for CD45, CD33, CD15, CD13 and HLA-DR and a Design and Methods diagnosis of acute myeloid leukemia was made. Cytogenetic analysis of bone marrow cells revealed a clonal Patients t(X;11)(q24;q23). The spinal fluid contained 14×109/L leuko- The study comprised three cases of AML in which an Xq24- cytes, morphologically described as reactive; immunocyto- 11q23 rearrangement was detected by karyotyping of the chemistry was unsuccessful. The patient was treated accord- leukemic cells. A summary of the clinical, cytogenetic, and ing to the Nordic protocol NOPHO-AML 93,1 and went into molecular genetic data is provided in Online Supplementary complete remission after the first course containing intrathecal Table S1. methotrexate and intravenous 6-thioguanine, cytarabine, etoposide and doxorubicin. This treatment was discontinued Patient 1 in August 1997 after a total of 6 courses without major com- A 17-month-old girl was admitted to the Portuguese plications. In April 2000, he was readmitted with a bone mar- Oncology Institute (Porto, Portugal) in September 2006 row relapse after a few weeks with infections and falling because of mucosal and cutaneous pallor and right leg pain, blood values. The leukemic blasts showed the same markers with refusal to walk. Peripheral blood analysis revealed leuko- as in 1997. cytosis, anemia, and thrombocytopenia, with 28% circulating He was reinduced with the same NOPHO protocol and blasts. The bone marrow was hypercellular containing 82% went into second complete remission after the first course. In blasts mainly positive for CD4, CD11b, CD11c, CD15, CD33, September 2000, after two more courses, he underwent bone CD64, CD65, HLA-DR, and LIS, and negative for CD2, cCD3, marrow transplantation from his older, HLA-identical sister CD13, CD14, CD16, CD34, CD36, CD56, CD79a, CD117, donor. There were no procedural complications and at last fol- and TdT. A diagnosis of acute myeloblastic leukemia with low-up, in October 2007, he was still in second complete maturation was established. Cytogenetic analysis showed evi- remission. The boy is active and with no sequelae. dence of a rearrangement involving the long arm of chromo- some 11 (11q23), with additional material of unknown origin Patient 3 in 11q23 and Xp11. She was treated according to the ELAM 02 This patient was a newborn boy, the third child of healthy protocol (aracytine, mitoxantrone and methotrexate) and parents, delivered at term in October 1997 after an uncompli- entered complete remission after induction chemotherapy. In cated pregnancy. The boy was transferred to the Department April 2007, she was submitted to allogeneic bone marrow of Paediatrics, St Olav University Hospital (Trondheim, transplantation and has no evidence of disease at the time of Norway) on suspicion of congenital leukemia. Initial physical writing. examination revealed widespread, firm, bluish cutaneous nod- ules, petecchiae and hepatosplenomegaly. The peripheral Patient 2 blood values were Hb 16.2 g/dL, platelets 100×109/L and WBC A previously healthy, 12-month-old boy was admitted to 340×109/L (90% with monoblastic morphology). The cere- the Rikshospitalet Department of Paediatrics (Oslo, Norway) brospinal fluid contained 101×109/L cells that by flow cyto- in March 1997 after a short history of skin bleedings. metric analysis were shown to be monoblasts. Peripheral blood analysis revealed leukocytosis (90% Immunophenotyping of peripheral blood confirmed a 90% myeloblasts), anemia and thrombocytopenia. The bone mar- population of cells expressing CD33, CD13, CD15, CD14 and row was hypercellular with more than 90% blasts that were partly CD24 and HLA-DR. Because of severe tumor lysis syn- Supplementary Table S1. Sequence of the primers used for the RNA and DNA analyses. Primer Target Sequence Position MLL-E5S MLL exon 5 5’-GAGGATCCTGCCCCAAAGAAAAG-3’ 3771_3793 MLL-E6S MLL exon 6 5’-GCAAACAGAAAAAAGTGGCTCCCCG-3’ 4048_4072 MLL-I6S-In MLL exon6/intron 6 5’-AAACCAAAAGAAAAGGTGAGGAGA-3’ 4095_4109/1_9 MLL-E7S-01 MLL exon 7 5’-CCTCCGGTCAATAAGCAGGAGAATG-3’ 4119_4143 MLL-E7S-02 MLL exon 7 5’-TCAGCACTCTCTCCAATGG-3’ 4162_4180 MLL-E8S MLL exon 8 5’-GCAGAAAATGTGTGGGAGATGGGAG-3’ 4254_4278 MLL-E8S-In MLL exon 8 5’-TTCCTATAACACCCAGGGTGGT-3’ 4300_4321 MLL-I6-01-O MLL intron 6 5’-CAAAGCAAAACACTGTCTCCAAAA-3’ 419_442 MLL-I6-01-In MLL intron 6 5’-AAAATTTAGGCTTGGCAAGGC-3’ 443_463 MLL-I6-02-O MLL intron 6 5’-GTTTCTTCCTTGTTGCTTTTCCC-3’ 1079_1101 MLL-I6-02-In MLL intron 6 5’-TGGCCCCACATGTTCTAGC-3’ 1109_1127 MLL-I8-01-O MLL intron 8 5’-AGAAATAAATACATGTTGGGTGGCA-3’ 438_462 MLL-I8-01-In MLL intron 8 5’-GAGGTGAAGGGAGGGTGTCTG-3’ 467_487 MLL-I8-02-O MLL intron 8 5’-CAGGCGGATCACAAGGTCA-3’ 878_896 MLL-I8-02-In1 MLL intron 8 5’-CACAGTGAAACCCCGTCTCTATT-3’ 921_943 MLL-I8-02-In2 MLL intron 8 5’-TCTGGAAGGATTCACACCAAAA-3’ 1331_1352 MLL-I8-03-O MLL intron 8 5’-TGTTGAGCAGTCAGTGAGACACAA-3’ 1970_1993 MLL-I8-03-In1 MLL intron 8 5’-CCCTGCCCACTTGCCAT-3’ 2012_2028 MLL-I8-03-In2 MLL intron 8 5’-TGCCTGCACTGCACTCCTAA-3’ 2394_2413 MLL-I8-04-O MLL intron 8 5’-GAGAATCGCTTGAACCCAGG-3’ 3113_3132 MLL-I8-04-In MLL intron 8 5’-GATCGCACCACTGCACCC-3’ 3156_3173 SEPT6-E2AS-01 SEPT6 exon 2 5’-CCTGGCTGACGGACTTATTCACC-3’ 361_383 SEPT6-E2AS-02 SEPT6 exon 2 5’-GCACAGGATGTTGAAGCAGA-3’ 387_406 SEPT6-E2AS-03 SEPT6 exon 2 5’-TTGCCCAAACCTGTCTCTCC-3’ 410_429 SEP06-I2LDAS-01 SEPT6 intron 1 5’-CAGCTATACCATCTCTGAAATGCAGGT-3’ 1657_1683 SEP06-I2LDAS-02 SEPT6 intron 1 5’-GGCCGATCAGTGCCCAGTGAATATGTG-3’ 4987_5013 SEP06-I2LDAS-03 SEPT6 intron 1 5’-ATAGATCGACCTTCCCTACGACTCTCTCCC-3’ 7718_7747 SEP06-I2LDAS-04 SEPT6 intron 1 5’-GCAAAGGTAGGAAGGACAGAAGGACAC-3’ 11924_11950 SEP06-I2LDAS-05 SEPT6 intron 1 5’-CCGTCAGCTTGGAAATCACAGATTCTT-3’ 17222_17248 SEP06-I2AS-01 SEPT6 intron 1 5’-ATACACACACAGACGCAGTCACAT-3’ 528_551 SEP06-I2AS-02 SEPT6 intron 1 5’-CACACCACAGAGGTGAGCACA-3’ 660_680 SEP06-I2AS-03 SEPT6 intron 1 5’-CACCTACAGGCCAGCCAACT-3’ 751_770 SEP06-I2AS-04 SEPT6 intron 1 5’-GCATCATCACAGAGAATGTCCC-3’ 1531_1552 SEP06-I2AS-05 SEPT6 intron 1 5’-GGAGAATCGCTTGAACCTGG-3’ 2427_2446 SEP06-I2AS-06 SEPT6 intron 1 5’-CACCATGTTGGCCAGGCT-3’ 3132_3149 SEP06-I2AS-07 SEPT6 intron 1 5’-GGCTTGCCCTGTGCCTT-3’ 3767_3783 SEP06-I2AS-08 SEPT6 intron 1 5’-AGTTTGGGAATACCTTTTTCCAGAG-3’ 5377_5401 SEP06-I2AS-09 SEPT6 intron 1 5’-TCGTATCACCCACTGACCAGC-3’ 6034_6054 SEP06-I2AS-10 SEPT6 intron 1 5’-TGGCTTGATGCTGGTCAGG-3’ 7332_7350 SEP06-I2AS-11 SEPT6 intron 1 5’-GGCAATATCTGAAGGGTTGTTTCT-3’ 7782_7805 SEP06-I2AS-12 SEPT6 intron 1 5’-GAGAATCGCTTGAACGCAGG-3’ 9896_9915 SEP06-I2AS-13 SEPT6 intron 1 5’-TGGGAACTGAGGGTGCATCT-3’ 10267_10286 SEP06-I2AS-14 SEPT6 intron 1 5’-GAGTAGTCGGTATGCTTCCCTATTG-3’ 10812_10836 SEP06-I2AS-15 SEPT6 intron 1 5’-TCAGTCCGCATTGTTCAGAGTT-3’ 11957_11978 SEP06-I2AS-16 SEPT6 intron 1 5’-CCACGCCCAGGTAATTTTTG-3’ 12695_12714 SEP06-I2AS-17 SEPT6 intron 1 5’-CTAGGAGCAGGAAGACATAGGAGG-3’ 13639_13662 SEP06-I2AS-18 SEPT6 intron 1 5’-AACAAAGTAAGATGCAAGATTCCCA-3’ 14411_14435 SEP06-I2AS-19 SEPT6 intron 1 5’-TGTGGTGAGCATTCAATCAGC-3’ 16021_16041 SEP06-I2AS-20 SEPT6 intron 1 5’-CCTTCCACATCTGCCATCTGA-3’ 17018_17038 E: exon; I: intron; S: sense; AS: antisense; O: outer; In: inner. drome and respiratory insufficiency, initially no bone marrow Chromosome banding and molecular cytogenetics sample was taken, but cytogenetic analysis of cells in the The diagnostic bone marrow samples (from patient 3, the peripheral blood revealed an insertion ins(X;11)(q24;q13q23). A diagnostic culture was of peripheral blood blasts) were cultured diagnosis of acute myeloid leukemia was made and treatment for 24 hours in RPMI 1640 medium with GlutaMAX-I was started according to the NOPHO-AML 93 protocol with a (Invitrogen, London, UK) supplemented with 20% fetal bovine prophase of low-dose cytarabine and intrathecal methotrexate.1 serum (Invitrogen, London, UK). Chromosome preparations Remission was achieved after the first A1 block. Because of were made by standard methods and banded by trypsin- prolonged pancytopenia during the treatment period, Leishman. Karyotypes were described according to the chemotherapy dosages had to be reduced. CNS-directed thera- International System for Human Cytogenetic Nomenclature.2 py was continued for one year. One
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